Luteinizing hormone releasing hormone (LHRH), also referred to as gonadotropin releasing hormone (GnRH), produced in the hypothalamic region, stimulates the release of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland. LH and FSH act on the gonads to stimulate the synthesis of steroid hormones and to stimulate gamete maturation. The release of LHRH, by stimulating the release of LH and FSH, controls the reproductive cycle in mammals.
Numerous LHRH analogues, both agonistic and antagonistic, have been synthesized. Low doses of LHRH and/or its agonistic analogues can stimulate ovulation and are useful in the treatment of hypothalamic and anovulatory infertility in the female due to hypothalamic deficiency in the synthesis or release, or both, of LHRH resulting in a hypogonal state. Additionally, these analogues stimulate spermatogenesis and androgen production in the male.
Paradoxically, larger doses of highly potent and long acting LHRH analogues have an opposite effect which blocks ovulation in the female and suppresses spermatogenesis and testosterone production in the male. Inhibitory (antagonistic) analogues of LHRH were developed for contraceptive purposes, by acting as a competetive inhibitor to endogenous LHRH at the pituitary receptor site. Nillius, S. J., "Luteinizing Hormone Releasing Hormone Analogues for Contraception," Clinics in Ob. Gyn. 11:551-572 (1984); Monroe, S. E. et al., "Ablation of Folliculogenesis in Women by a Single Dose of Gonadotropin-Releasing Hormone Agonist: Significance of Time in Cycle," Fertility Sterility 43:361-368 (1985); Lemay, A. L. et al., "Inhibition of Ovulation During Discontinuous Intranasal Luteinizing Hormone-Releasing Hormone Agonist Dosing in Combination with Gestagen-Induced Bleeding," Fertility and Sterility 43:868-877 (1985); Gudmundsson, J. A. et al., "Inhibition of Ovulation by Intranasal Nafarelin, A New Superactive Agonist of GnRH," Contraception 30: 107-114 (1984); and Kuhl, H. et al., "Contraception with an LHRH Agonist: Effect on Gonadotropin and Steroid Secretion Patterns," Clinical Endocrin. 21:179-188 (1984).
Administration of large doses of LHRH analogues produce a selective, reversible and complete biochemical castration at the pituitary level. These LHRH analogues have had several therapeutic applications in medicine. The first of these applications was their use in treating precocious puberty. Another application was their use to suppress uterine fibroids. In addition, prostate cancer, and other hormonally sensitive cancers, such as breast cancer, endometriosis, and polycystic ovarian disease all have proven to be suppressed during LHRH analogue administration. Filicori, M. et al., "A Conservative Approach to the Management of Uterine Leiomyoma: Pituitary Desentyation by an LHRH Analogue," Am. J. Ob. Gyn., 6:726 (1983); Lemay, H. et al., "Reversible Hypogonadism Induced by a Luteinizing Hormone Releasing Hormone (LHRH) Agonist (Buserelin) as a New Therapeutic Approach for Endometriosis," Fertil. Steril., 41:863 (1984); Schriock, E. et al., "Treatment of Endometriosis with a Potent Agonist of Gonadotropin-Releasing Hormone (Nafarelin)," Fertil. Steril., 44:583; and Chang, R. J. et al., "Steroid Secretors in Polycytic Ovarian Disease after Ovarian Suppression by a Long-Acting Gonadotropin-Releasing Hormone Agonist," J. Chem. Endomel. Metab., 56:897 (1983).
The central problem now emerging with this prolonged treatment relates to the nearly total biochemical castration produced by these LHRH analogues. The pituitary quiescence induced by LHRH analogues results in a total suppression of gonadotropins and ovarian steroid secretions (estrodiol and progesterone). This pituitary quiescence in women leads to the side effects of estrogen deficiency, including hot flashes, vaginal dryness, and, most ominously, the possibility of osteopenia and osteoporosis. These side effects seen with prolonged LHRH therapy are thus comparable to those seen in menopausal women with a similar degree of estrogen deficiency. Unfortunately, these long term side effects of using LHRH analogues may limit their widespread applicability as contraceptives. Thus, it would be desirable to have a contraceptive using LHRH and/or its analogues (either agonists and/or antagonists) that can be administered in a safe, physiologic, and convenient mechanism, without the side effects relating to deprivation of the sex steroid hormones.